Compact apparatus for noninvasive measurement of glucose through near-infrared spectroscopy

ABSTRACT

The invention involves the monitoring of a biological parameter through a compact analyzer. The preferred apparatus is a spectrometer based system that is attached continuously or semi-continuously to a human subject and collects spectral measurements that are used to determine a biological parameter in the sampled tissue. The preferred target analyte is glucose. The preferred analyzer is a near-IR based glucose analyzer for determining the glucose concentration in the body.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.10/472,856 filed Mar. 3, 2003, which claims:

-   -   priority to PCT application no. PCT/US03/07065 filed Mar. 7,        2003, which claims benefit of U.S. provisional patent        application No. 60/362,885, filed on Mar. 8, 2002;    -   benefit of U.S. provisional patent application No. 60/362,899,        filed on Mar. 8, 2002; and    -   benefit of U.S. provisional patent application No. 60/448,840        filed on Feb. 19, 2003;    -   each of which is incorporated herein in its entirety by this        reference thereto.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates generally to the noninvasive measurement ofbiological parameters through near-infrared spectroscopy. In particular,an apparatus and a method are disclosed for noninvasively, andcontinuously or semi-continuously, monitoring a biological parameter,such as glucose in tissue.

2. Discussion of the Prior Art

Diabetes

Diabetes is a chronic disease that results in improper production anduse of insulin, a hormone that facilitates glucose uptake into cells.Diabetes can be broadly categorized into four forms: diabetes, impairedglucose tolerance, normal physiology, and hyperinsulinemia(hypoglycemia). While a precise cause of diabetes is unknown, geneticfactors, environmental factors, and obesity appear to play roles.Diabetics have increased risk in three broad categories: cardiovascularheart disease, retinopathy, and neuropathy. Diabetics may have one ormore of the following complications: heart disease and stroke, highblood pressure, kidney disease, neuropathy (nerve disease andamputations), retinopathy, diabetic ketoacidosis, skin conditions, gumdisease, impotence, and fetal complications. Diabetes is a leading causeof death and disability worldwide.

Diabetes Prevalence and Trends

Diabetes is a common and growing disease. The World Health Organization(WHO) estimates that diabetes currently afflicts one hundred fifty-fourmillion people worldwide. Fifty-four million diabetics live in developedcountries. The WHO estimates that the number of people with diabeteswill grow to three hundred million by the year 2025. In the UnitedStates, 15.7 million people or 5.9% of the population are estimated tohave diabetes. Within the United States, the prevalence of adultsdiagnosed with diabetes increased by six percent in 1999 and rose bythirty-three percent between 1990 and 1998. This corresponds toapproximately eight hundred thousand new cases every year in America.The estimated total cost to the United States economy alone exceeds $90billion per year (Diabetes Statistics. Bethesda, Md.: National Instituteof Health, Publication No. 98-3926, Nov. 1997).

Long-term clinical studies show that the onset of diabetes relatedcomplications can be significantly reduced through proper control ofblood glucose concentrations (The Diabetes Control and ComplicationsTrial Research Group. The effect of intensive treatment of diabetes onthe development and progression of long-term complications ininsulin-dependent diabetes mellitus. N Eng J of Med 1993;329:977-86;U.K. Prospective Diabetes Study (UKPDS) Group, “Intensive blood-glucosecontrol with sulphonylureas or insulin compared with conventionaltreatment and risk of complications in patients with type 2 diabetes,”Lancet, vol. 352, pp. 837-853, 1998; Ohkubo, Y., H. Kishikawa, E. Araki,T. Miyata, S. Isami, S. Motoyoshi, Y. Kojima, N. Furuyoshi, and M.Shichizi, “Intensive insulin therapy prevents the progression ofdiabetic microvascular complications in Japanese patients withnon-insulin-dependent diabetes mellitus: a randomized prospective 6-yearstudy,” Diabetes Res Clin Pract, vol. 28, pp. 103-117, 1995). A vitalelement of diabetes management is the self-monitoring of blood glucoselevels by diabetics in the home environment. However, current monitoringtechniques discourage regular use due to the inconvenient and painfulnature of drawing blood through the skin prior to analysis (The DiabetesControl and Complication Trial Research Group, “The effect of intensivetreatment of diabetes on the development and progression of long-termcomplications of insulin-dependent diabetes mellitus”, N. Engl. J. Med.,329, 1993, 997-1036). Unfortunately, recent reports indicate that evenperiodic measurement of glucose by individuals with diabetes, (e.g.seven times per day) is insufficient to detect important glucosefluctuations and properly manage the disease. In addition, nocturnalmonitoring of glucose levels is of significant value but is difficult toperform due to the state of existing technology. Therefore, a devicethat provides noninvasive, automatic, and nearly continuous measurementsof glucose levels would be of substantial value to people with diabetes.Implantable glucose analyzers eventually coupled to an insulin deliverysystem providing an artificial pancreas are also being pursued.

DESCRIPTION OF RELATED TECHNOLOGY

Common technologies are used to analyze the blood glucose concentrationof samples collected by venous draw and with capillary stick approaches.Glucose analysis includes techniques such as calorimetric and enzymaticglucose analysis. Many of the invasive, traditional invasive,alternative invasive, and minimally invasive glucose analyzers use thesetechnologies. The most common enzymatic based glucose analyzers useglucose oxidase, which catalyzes the reaction of glucose with oxygen toform gluconolactone and hydrogen peroxide, equation 1. Glucosedetermination may be achieved by techniques based upon depletion ofoxygen in the sample, through the changes in sample pH, or via theformation of hydrogen peroxide. A number of calorimetric andelectro-enzymatic techniques further use the reaction products as astarting reagent. For example, hydrogen peroxide reacts in the presenceof platinum to form the hydrogen ion, oxygen, and current any of whichmay be used to determine the glucose concentration, equation 2.glucose+O₂→gluconolactone+H₂O₂   eq. 1H₂O₂→2H⁺+O₂+2e⁻  eq. 2

Due to the wide and somewhat loose terminology in the field, the termstraditional invasive, alternative invasive, noninvasive, and implantableare here outlined:

Traditional Invasive Glucose Determination

There are three major categories of traditional (classic) invasiveglucose determinations. The first two methodologies use blood drawn witha needle from an artery or vein, respectively. The third group consistsof capillary blood obtained via lancet from the fingertip or toes. Overthe past two decades, this last method has become the most common methodfor self-monitoring of blood glucose at home, at work, or in publicsettings.

Alternative Invasive Glucose Determination

There are several alternative invasive methods of determining glucoseconcentrations.

A first group of alternative invasive glucose analyzers have a number ofsimilarities to traditional invasive glucose analyzers. One similarityis that blood samples are acquired with a lancet. Obviously, this formof alternative invasive glucose determination may not be used to collectvenous or arterial blood for analysis, but may be used to collectcapillary blood samples. A second similarity is that the blood sample isanalyzed using chemical analyses that are similar to the calorimetricand enzymatic analyses describe above. The primary difference is that inan alternative invasive glucose determination the blood sample is notcollected from the fingertip or toes. For example, according to packagelabeling the TheraSense® FreeStyle Meter™ may be used to collect andanalyze blood from the forearm. This is an alternative invasive glucosedetermination due to the location of the lancet draw.

In this first group of alternative invasive methods based upon blooddraws with a lancet, a primary difference between the alternativeinvasive and traditional invasive glucose determination is the locationof blood acquisition from the body. Additional differences includefactors such as the gauge of the lancet, the depth of penetration of thelancet, timing issues, the volume of blood acquired, and environmentalfactors such as the partial pressure of oxygen, altitude, andtemperature. This form of alternative invasive glucose determinationincludes samples collected from the palmar region, base of thumb,forearm, upper arm, head, earlobe, torso, abdominal region, thigh, calf,and plantar region.

A second group of alternative invasive glucose analyzers aredistinguished by their mode of sample acquisition. This group of glucoseanalyzers has a common characteristic of acquiring a biological samplefrom the body or modifying the surface of the skin to gather a samplewithout use of a lancet for subsequent analysis. For example, a laserporation based glucose analyzer would use a burst or stream of photonsto create a small hole in the surface of the skin. A sample of basicallyinterstitial fluid would collect in the resulting hole. Subsequentanalysis of the sample for glucose would constitute an alternativeinvasive glucose analysis whether or not the sample was actually removedfrom the created hole. A second common characteristic is that a deviceand algorithm are used to determine glucose from the sample.

A number of methodologies exist for the collection of the sample foralternative invasive measurements including laser poration, appliedcurrent, and suction. The most common are summarized here:

A. Laser poration: In these systems, photons of one or more wavelengthsare applied to skin creating a small hole in the skin barrier. Thisallows small volumes of interstitial fluid to become available to anumber of sampling techniques.

B. Applied current: In these systems, a small electrical current isapplied to the skin allowing interstitial fluid to permeate through theskin.

C. Suction: In these systems, a partial vacuum is applied to a localarea on the surface of the skin. Interstitial fluid permeates the skinand is collected.

For example, a device that acquires a sample via iontophoresis, such asCygnus'® GlucoWatch™, is an alternative invasive technique.

In all of these techniques, the analyzed sample is interstitial fluid.However, some of the techniques can be applied to the skin in a fashionthat draws blood. Herein, the term alternative invasive includestechniques that analyze biosamples such as interstitial fluid, wholeblood, mixtures of interstitial fluid and whole blood, and selectivelysampled interstitial fluid. An example of selectively sampledinterstitial fluid is collected fluid in which large or less mobileconstituents are not fully represented in the resulting sample. For thisgroup of alternative invasive glucose analyzers sampling sites include:the hand, fingertips, palmar region, base of thumb, forearm, upper arm,head, earlobe, eye, chest, torso, abdominal region, thigh, calf, foot,plantar region, and toes. In this document, any technique that drawsbiosamples from the skin without the use of a lancet on the fingertip ortoes is referred to as an alternative invasive technique.

In addition, it is recognized that the alternative invasive systems eachhave different sampling approaches that lead to different subsets of theinterstitial fluid being collected. For example, large proteins mightlag behind in the skin while smaller, more diffusive, elements may bepreferentially sampled. This leads to samples being collected withvarying analyte and interferent concentrations. Another example is thata mixture of whole blood and interstitial fluid may be collected.Another example is that a laser poration method can result in blooddroplets. These techniques may be used in combination. For example theSoft-Tact, SoftSense in Europe, applies a suction to the skin followedby a lancet stick. Despite the differences in sampling, these techniquesare referred to as alternative invasive techniques sampling interstitialfluid.

Sometimes, the literature refers to the alternative invasive techniqueas an alternative site glucose determination or as a minimally invasivetechnique. The minimally invasive nomenclature derives from the methodby which the sample is collected. In this document, the alternative siteglucose determinations that draw blood or interstitial fluid, even ¼microliter, are considered to be alternative invasive glucosedetermination techniques as defined above. Examples of alternativeinvasive techniques include the TheraSense® FreeStyle™ when not samplingfingertips or toes, the Cygnus® GlucoWatch™, the One Touch® Ultra™, andequivalent technologies.

Biosamples collected with alternative invasive techniques are analyzedvia a large range of technologies. The most common of these technologiesare summarized below:

A. Conventional: With some modification, the interstitial fluid samplesmay be analyzed by most of the technologies used to determine glucoseconcentrations in serum, plasma, or whole blood. These includeelectrochemical, electroenzymatic, and colorimetric approaches. Forexample, the enzymatic and colorimetric approaches described above mayalso be used to determine the glucose concentration in interstitialfluid samples.

B. Spectrophotometric: A number of approaches, for determining theglucose concentration in biosamples, have been developed that are basedupon spectrophotometric technologies. These techniques include: Ramanand fluorescence, as well as techniques using light from the ultravioletthrough the infrared [ultraviolet (200 to 400 nm), visible (400 to 700nm), near-IR (700 to 2500 nm or 14,286 to 4000 cm⁻¹), and infrared (2500to 14,285 nm or 4000 to 700 cm⁻¹)]. In this document, an invasiveglucose analyzer is the genus of both the traditional invasive glucoseanalyzer species and the alternative invasive glucose analyzer species.

Noninvasive Glucose Determination

There exist a number of noninvasive approaches for glucosedetermination. These approaches vary widely, but have at least twocommon steps. First, an apparatus is used to acquire a reading from thebody without obtaining a biological sample. Second, an algorithm is usedto convert this reading into a glucose determination.

One species of noninvasive glucose analyzers are those based upon thecollection and analysis of spectra. Typically, a noninvasive apparatususes some form of spectroscopy to acquire the signal or spectrum fromthe body. Used spectroscopic techniques include but are not limited toRaman, fluorescence, as well as techniques using light from ultravioletthrough the infrared [ultraviolet (200 to 400 nm), visible (400 to 700nm), near-IR (700 to 2500 nm or 14,286 to 4000 cm⁻¹), and infrared (2500to 14,285 nm or 4000 to 700 cm⁻¹)]. A particular range for noninvasiveglucose determination in diffuse reflectance mode is about 1100 to 2500nm or ranges therein (Hazen, Kevin H. “Glucose Determination inBiological Matrices Using Near-Infrared Spectroscopy”, doctoraldissertation, University of Iowa, 1995). It is important to note, thatthese techniques are distinct from the traditionally invasive andalternative invasive techniques listed above in that the sample analyzedis a portion of the human body in-situ, not a biological sample acquiredfrom the human body.

Typically, three modes are used to collect noninvasive scans:transmittance, transflectance, and/or diffuse reflectance. For examplethe light, spectrum, or signal collected may be light transmittingthrough a region of the body, diffusely transmitting, diffuselyreflected, or transflected. Transflected here refers to collection ofthe signal not at the incident point or area (diffuse reflectance), andnot at the opposite side of the sample (transmittance), but rather atsome point or region of the body between the transmitted and diffusereflectance collection area. For example, transflected light enters thefingertip or forearm in one region and exits in another region. Whenusing the near-IR, the transflected radiation typically radiallydisperses 0.2 to 5 mm or more away from the incident photons dependingon the wavelength used. For example, light that is strongly absorbed bythe body such as light near the water absorbance maxima at 1450 or 1950nm must be collected after a small radial divergence in order to bedetected and light that is less absorbed such as light near waterabsorbance minima at 1300, 1600, or 2250 nm may be collected at greaterradial or transflected distances from the incident photons.

Noninvasive techniques are not limited to the fingertip. Other regionsor volumes of the body subjected to noninvasive measurements are: ahand, finger, palmar region, base of thumb, forearm, volar aspect of theforearm, dorsal aspect of the forearm, upper arm, head, earlobe, eye,tongue, chest, torso, abdominal region, thigh, calf, foot, plantarregion, and toe. It is important to note that noninvasive techniques donot have to be based upon spectroscopy. For example, a bioimpedencemeter would be a noninvasive device. In this document, any device thatreads glucose from the body without penetrating the skin and collectinga biological sample is referred to as a noninvasive glucose analyzer.For the purposes of this document, X-rays and MRI's are not consideredto be defined in the realm of noninvasive technologies.

Implantable Sensor for Glucose Determination

There exist a number of approaches for implanting a glucose sensor intothe body for glucose determination. These implantables may be used tocollect a sample for further analysis or may acquire a reading of thesample directly or based upon direct reactions occurring with glucose.Two categories of implantable glucose analyzers exist: short-term andlong-term.

In this document, a device or a collection apparatus is referred to as ashort-term implantable (as opposed to a long-term implantable) if partof the device penetrates the skin for a period of greater than threehours and less than one month. For example, a wick placed subcutaneouslyto collect a sample overnight that is removed and analyzed for glucosecontent representative of the interstitial fluid glucose concentrationis referred to as a short term implantable. Similarly, a biosensor orelectrode placed under the skin for a period of greater than three hoursthat reads directly or based upon direct reactions occurring withglucose concentration or level is referred to as a short-termimplantable device. Conversely, devices such as a lancet, appliedcurrent, laser poration, or suction are referred to as either atraditional invasive or alternative invasive technique as they do notfulfill both the three hour and penetration of skin parameters. Anexample of a short-term implantable glucose analyzer is MiniMed's®continuous glucose monitoring system. In this document, long-termimplantables are distinguished from short-term implantables by havingthe criteria that they must both penetrate the skin and be used for aperiod of one month or longer. Long term implantables may be in the bodyfor greater than one month, one year, or many years.

Implantable glucose analyzers vary widely, but have at least severalsteps in common. First, at least part of the device penetrates the skin.More commonly, the entire device is imbedded into the body. Second, theapparatus is used to acquire either a sample of the body or a signalrelating directly or based upon direct reactions occurring with theglucose concentration within the body. If the implantable devicecollects a sample, readings or measurements on the sample may becollected after removal from the body. Alternatively, readings may betransmitted out of the body by the device or used for such purposes asinsulin delivery while in the body. Third, an algorithm is used toconvert the signal into a reading directly or based upon directreactions occurring with the glucose concentration. An implantableanalyzer may read from one or more of a variety of body fluids ortissues including but not limited to: arterial blood, venous blood,capillary blood, interstitial fluid, and selectively sampledinterstitial fluid. An implantable analyzer may also collect glucoseinformation from skin tissue, cerebral spinal fluid, organ tissue, orthrough an artery or vein. For example, an implantable glucose analyzermay be placed transcutaneously, in the peritoneal cavity, in an artery,in muscle, or in an organ such as the liver or brain. The implantableglucose sensor may be one component of an artificial pancreas.

Description of Related Technology

One class of alternative invasive continuous glucose monitoring systemsare those based upon iontophoresis. Using the iontophoresis process,uncharged molecules such as glucose may be moved across the skin barrierwith the application of a small electric current. Several patents andpublications in this area are available (Tamada, J. A., S. Garg, L.Jovanovic, K. R. Pitzer, S. Fermi, R. O. Potts, “Noninvasive GlucoseMonitoring Comprehensive Clinical Results,” JAMA, Vol. 282, No. 19, pp.1839-1844, Nov. 17, 1999; Berner, Bret; Dunn, Timothy c.; Farinas,Kathleen C.; Garrison, Michael D.; Kurnik, Ronald T.; Lesho, Matthew J.;Potts, Russell O.; Tamada, Janet A.; Tierney, Michael J. “SignalProcessing for Measurement of Physiological Analysis”, U.S. Pat. No.6,233,471, May 15, 2001; Dunn, Timothy C.; Jayalakshmi, Yalia; Kurnik,Ronald T.; Lesho, Matthew J.; Oliver, Jonathan James; Potts, Russell O.;Tamada, Janet A.; Waterhouse, Steven Richard; Wei, Charles W.“Microprocessors for use in a Device Predicting Physiological Values”,U.S. Pat. No. 6,326,160, Dec. 4, 2001; Kurnik, Ronald T. “Method andDevice for Predicting Physiological Values”, U.S. Pat. No. 6,272,364,Aug. 7, 2001; Kurnik, Ronald T.; Oliver, Jonathan James; Potts, RussellO.; Waterhouse, Steven Richard; Dunn, Timothy C.; Jayalakshmi, Yalia;Lesho, Matthew J.; Tamada, Janet A.; Wei, Charles W. “Method and Devicefor Predicting Physiological Values”, U.S. Pat. No. 6,180,416, Jan. 30,2001; Tamada, Janet A.; Garg, Satish; Jovanovic, Lois; Pitzer, KennethR.; Fermi, Steve; Potts, Russell O. “Noninvasive Glucose Monitoring”,JAMA, 282, 1999, 1839-1844; Sage, Burton H. “FDA Panel Approves Cygnus'sNoninvasive GlucoWatch™”, Diabetes Technology & Therapeutics, 2, 2000,115-116; and “GlucoWatch Automatic Glucose Biographer and AutoSensors”,Cygnus Inc., Document #1992-00, Rev. March 2001) The Cygnus GlucoseWatch® uses this technology. The GlucoWatch® provides only one readingevery twenty minutes, each delayed by at least ten minutes due to themeasurement process. The measurement is made through an alternativeinvasive electrochemical-enzymatic sensor on a sample of interstitialfluid which is drawn through the skin using iontophoresis. Consequently,the limitations of the device include the potential for significant skinirritation, collection of a biohazard, and a limit of three readings perhour.

One class of semi-implantable glucose analyzers are those based uponopen-flow microperfusion (Trajanowski, Zlatko; Brunner, Gernot A.;Schaupp, Lucas; Ellmerer, Martin; Wach, Paul; Pieber, Thomas R,;Kotanko, Peter; Skrabai, Falko “Open-Flow Microperfusion of SubcutaneousAdipose Tissue for ON-Line Continuous Ex Vivo Measurement of GlucoseConcentration”, Diabetes Care, 20, 1997, 1114-1120). Typically thesesystems are based upon biosensors and amperometric sensors (Trajanowski,Zlatko; Wach, Paul; Gfrerer, Robert “Portable Device for ContinuousFractionated Blood Sampling and Continuous ex vivo Blood GlucoseMonitoring”, Biosensors and Bioelectronics, 11, 1996, 479-487). A commonissue with semi-implantable and implantable devices is coating byproteins. The MiniMed® continuous glucose monitoring system, ashort-term implantable, is the first commercially availablesemi-continuous glucose monitor in this class. The MiniMed® system iscapable of providing a glucose profile for up to seventy-two hours. Thesystem records a glucose value every five minutes. The technology behindthe MiniMed® system relies on a probe being invasively implanted into asubcutaneous region followed by a glucose oxidase based reactionproducing hydrogen peroxide, which is oxidized at a platinum electrodeto produce an analytical current. Notably, the MiniMed® systemautomatically shifts glucose determinations by ten minutes in order toaccommodate for a potential dynamic lag between the blood andinterstitial glucose (Gross, Todd M.; Bode, Bruce W.; Einhorn, Daniel;Kayne, David M.; Reed, John H.; White, Neil H.; Mastrototaro, John J.“Performance Evaluation of the MiniMed Continuous Glucose MonitoringSystem During Patient Home Use”, Diabetes Technology & Therapeutics, 2,2000, 49-56.; Rebrin, Kerstin; Steil, Gary M.; Antwerp, William P. Van;Mastrototaro, John J. “Subcutaneous Glucose Predicts Plasma GlucoseIndependent of Insulin: Implications for Continuous Monitoring”, Am., J.Physiol., 277, 1999, E561-E571, 0193-1849/99, The American PhysiologicalSociety, 1999).

Other approaches, such as the continuous monitoring system reported byGross, et. al. (Gross, T. M., B. W. Bode, D. Einhorn, D. M. Kayne, J. H.Reed, N. H. White and J. J. Mastrototaro, “Performance Evaluation of theMiniMed® Continuous Glucose Monitoring System During Patient Home Use,”Diabetes Technology & Therapeutics, Vol. 2, Num. 1, 2000), involve theimplantation of a sensor in tissue with a transcutaneous externalconnector. Inherent in these approaches are health risks due to thesensor implantation, infections, patient inconvenience, and measurementdelay.

Another approach towards continuous glucose monitoring is through theuse of fluorescence. For example Sensors for Medicine and ScienceIncorporated (S4MS) is developing a glucose selective indicator moleculecombined into an implantable device that is coupled via telemetry to anexternal device. The device works via an indicator molecule thatreversibly binds to glucose. With an LED for excitation, the indicatormolecule fluoresces in the presence of glucose. This device is anexample of a short-term implantable with development towards a long-termimplantable (Colvin, Arthur E. “Optical-Based Sensing Devices Especiallyfor In-Situ Sensing in Humans”, U.S. Pat. No. 6,304,766, Oct. 16, 2001;Colvin, Arthur E.; Dale, Gregory A.; Zerwekh, Samuel, Lesho, Jeffery C.;Lynn, Robert W. “Optical-Based Sensing Devices”, U.S. Pat. No.6,330,464, Dec. 11, 2001; Colvin, Arthur E.; Daniloff, George Y.;Kalivretenos, Aristole G.; Parker, David; Ullman, Edwin E.;Nikolaitchik, Alexandre V. “Detection of Analytes by fluorescentLanthanide Metal Chelate Complexes Containing Substituted Ligands”, U.S.Pat. No. 6,334,360, Feb. 5, 2002; and Lesho, Jeffery “Implanted SensorProcessing System and Method for Processing Implanted Sensor Output”,U.S. Pat. No. 6,400,974, Jun. 4, 2002).

Notably, none of these technologies are noninvasive. Further, none ofthese technologies offer continuous glucose determination.

Another technology, near-infrared spectroscopy, provides the opportunityto measure glucose noninvasively with a relativity short samplinginterval. This approach involves the illumination of a spot on the bodywith near-infrared electromagnetic radiation (light in the wavelengthrange 700 to 2500 nm). The incident light is partially absorbed andscattered, according to its interaction with the constituents of thetissue. The actual tissue volume that is sampled is the portion ofirradiated tissue from which light is diffusely reflected, transflected,or transmitted by the sample and optically coupled to the spectrometerdetection system. The signal due to glucose is extracted from thespectral measurement through various methods of signal processing andone or more mathematical models. The models are developed through theprocess of calibration on the basis of an exemplary set of spectralmeasurements and associated reference blood glucose values (thecalibration set) based on an analysis of capillary (fingertip),alternative invasive samples, or venous blood. To date, only discreteglucose determinations have been reported using near-IR technologies.

There exists a body of work on noninvasive glucose determination usingnear-IR technology, the most pertinent of which are referred here(Robinson, Mark Ries; Messerschmidt, Robert G “Method for Non-invasiveBlood Analyte Measurement with Improved Optical Interface”, U.S. Pat.No. 6,152,876, Nov. 28, 2000; Messerschmidt, Robert G.; Robinson, MarkRies “Diffuse Reflectance Monitoring Apparatus”, U.S. Pat. No.5,935,062, Aug. 10, 1999; Messerschmidt, Robert G. “Method forNon-invasive Analyte Measurement with Improved Optical Interface”, U.S.Pat. No. 5,823,951, Oct. 20, 1998; Messerschmidt, Robert G. “Method forNon-invasive Blood Analyte Measurement with Improved Optical Interface”,U.S. Pat. No. 5,655,530; Rohrscheib, Mark; Gardner, Craig; Robinson,Mark R. “Method and Apparatus for Non-invasive Blood Analyte Measurementwith Fluid Compartment Equilibration”, U.S. Pat. No. 6,240,306, May 29,2001; Messerschmidt, Robert G.; Robinson, Mark Ries “Diffuse ReflectanceMonitoring Apparatus”, U.S. Pat. No. 6,230,034, May 8, 2001; Barnes,Russell H.; Brasch, Jimmie W. “Non-invasive Determination of GlucoseConcentration in Body of Patients”, U.S. Pat. No. 5,070,874, Dec. 10,1991; and Hall, Jeffrey; Cadell, T. E. “Method and Device for MeasuringConcentration Levels of Blood Constituents Non-invasively”, U.S. Pat.No. 5,361,758, Nov. 8, 1994). Several Sensys Medical patents alsoaddress noninvasive glucose analyzers: Schlager, Kenneth J.“Non-invasive Near Infrared Measurement of Blood AnalyteConcentrations”, U.S. Pat. No. 4,882,492, Nov. 21, 1989.; Malin,Stephen; Khalil, Gamal “Method and Apparatus for Multi-Spectral Analysisin Noninvasive Infrared Spectroscopy”, U.S. Pat. No. 6,040,578, Mar. 21,2000; Garside, Jeffrey J.; Monfre, Stephen; Elliott, Barry C.; Ruchti,Timothy L.; Kees, Glenn Aaron “Fiber Optic Illumination and DetectionPatterns, Shapes, and Locations for Use in Spectroscopic Analysis”, U.S.Pat. No. 6,411,373, Jun. 25, 2002; Blank, Thomas B.; Acosta, George;Mattu, Mutua; Monfre, Stephen L. “Fiber Optic Probe and PlacementGuide”, U.S. Pat. No. 6,415,167, Jul. 2, 2002; and Wenzel, Brian J.;Monfre, Stephen L.; Ruchti, Timothy L.; Meissner, Ken; Grochocki, Frank“A Method for Quantification of Stratum Corneum Hydration Using DiffuseReflectance Spectroscopy”, U.S. Pat. No. 6,442,408, Aug. 27, 2002.

Mode of Analysis

A measurement of glucose is termed “direct” when the net analyte due tothe absorption of light by glucose in the tissue is extracted from thespectral measurement through various methods of signal processing and/orone or more mathematical models. In this document, an analysis isreferred to as direct if the analyte of interest is involved in achemical reaction. For example, in equation 1 glucose reacts with oxygenin the presence of glucose oxidase to form hydrogen peroxide andgluconolactone. The reaction products may be involved in subsequentreactions such as that in equation 2. The measurement of any reactioncomponent or product is a direct reading of glucose, herein. In thisdocument, a direct reading of glucose would also entail any reading inwhich the electromagnetic signal generated is due to interaction withglucose or a compound of glucose. For example, the fluorescence approachlisted above by Sensors for Medicine and Science is termed a directreading of glucose, herein.

A measurement of glucose is termed “indirect” when movement of glucosewithin the body affects physiological parameters. In brief, an indirectglucose determination may be based upon a change in glucoseconcentration causing an ancillary physiological, physical, or chemicalresponse that is relatively large. A key finding related to thenoninvasive measurement of glucose is that a major physiologicalresponse accompanies changes in glucose and can be detectednoninvasively through the resulting changes in tissue properties.

An indirect measurement of blood glucose through assessment ofcorrelated tissue properties and/or physiological responses requires adifferent strategy when compared with the direct measurement of glucosespectral signals. Direct measurement of glucose requires the removal ofspectral variation due to other constituents and properties in order toenhance the net analyte signal of glucose. Because the signal directlyattributable to glucose in tissue is small, an indirect calibration tocorrelated constituents or properties, e.g. the physiological responseto glucose, is attractive due to a gain in relative signal size. Forexample, changes in the concentration of glucose alters the distributionof water in the various tissue compartments. Because water has a largeNIR signal that is relatively easy to measure compared to glucose, acalibration based at least in part on the compartmental activity ofwater has a magnified signal related to glucose. An indirect measurementmay be referred to as a measurement of an ancillary effect of the targetanalyte. An indirect measurement means that an ancillary effect due tochanges in glucose concentration is being measured.

A major component of the body is water. A re-distribution of waterbetween the vascular and extravascular compartments and the intra- andextra-cellar compartments is observed as a response to differences inglucose concentrations in the compartments during periods of changingblood glucose. Water, among other analytes, is shifted between thetissue compartments to equilibrate the osmotic imbalance related tochanges in glucose concentration as predicted by Fick's law of diffusionand the fact that water diffuses much faster in the body than doesglucose. Therefore, a strategy for the indirect measurement of glucosethat exploits the near-infrared signal related to fluid re-distributionis to design measurement protocols that force maximum correlationbetween blood glucose and the re-distribution of fluids. This is theopposite strategy of the one required for the direct measurement ofblood glucose in which the near-infrared signals directly related toglucose and fluids must be discriminated and attempts at equalizingglucose in the body compartment are made. A reliable indirectmeasurement of glucose based at least in part in the re-distribution offluids and analytes (other than glucose) and related changes in theoptical properties of tissue requires that the indirect signals arelargely due to the changing blood glucose concentration. Other variablesand sources that modify or change the indirect signals of interestshould be prevented or minimized in order to ensure a reliable indirectmeasurement of glucose.

One interference to a determination of blood/tissue glucoseconcentration measured indirectly is a rapid change in blood perfusion,which also leads to fluid movement between the compartments. This typeof physiological change interferes constructively or destructively withthe analyte signal of the indirect measurement. In order to preserve ablood glucose/fluid shift calibration it is beneficial to control otherfactors influencing fluid shifts including local blood perfusion.

Near-IR Instrumentation

A number of technologies have been reported for measuring glucosenoninvasively that involve the measurement of a tissue related variable.One species of noninvasive glucose analyzers use some form ofspectroscopy to acquire the signal or spectrum from the body. Examplesinclude but are not limited to far-infrared absorbance spectroscopy,tissue impedance, Raman, and fluorescence, as well as techniques usinglight from the ultraviolet through the infrared [ultraviolet (200 to 400nm), visible (400 to 700 nm), near-IR (700 to 2500 nm or 14,286 to 4000cm⁻¹), and infrared (2500 to 14,285 nm or 4000 to 700 cm⁻¹)]. Aparticular range for noninvasive glucose determination in diffusereflectance mode is about 1100 to 2500 nm or ranges therein (Hazen,Kevin H. “Glucose Determination in Biological Matrices UsingNear-Infrared Spectroscopy”, doctoral dissertation, University of Iowa,1995). It is important to note, that these techniques are distinct frominvasive techniques in that the sample analyzed is a portion of thehuman body in-situ, not a biological sample acquired from the humanbody. The actual tissue volume that is sampled is the portion ofirradiated tissue from which light is diffusely reflected, transflected,or diffusely transmitted to the spectrometer detection system. Thesetechniques share the common characteristic that a calibration isrequired to derive a glucose concentration from subsequent collecteddata.

A number of spectrometer configurations exist for collecting noninvasivespectra of regions of the body. Typically a spectrometer has one or morebeam paths from a source to a detector. A light source may include ablackbody source, a tungsten-halogen source, one or more LED's, or oneor more laser diodes. For multi-wavelength spectrometers a wavelengthselection device may be used or a series of optical filters may be usedfor wavelength selection. Wavelength selection devices includedispersive elements such as one or more plane, concave, ruled, orholographic grating. Additional wavelength selective devices include aninterferometer, successive illumination of the elements of an LED array,prisms, and wavelength selective filters. However, variation of thesource such as varying which LED or diode is firing may be used.Detectors may be in the form of one or more single element detectors orone or more arrays or bundles of detectors. Detectors may includeInGaAs, extended InGaAs, PbS, PbSe, Si, MCT, or the like. Detectors mayfurther include arrays of InGaAs, extended InGaAs, PbS, PbSe, Si, MCT,or the like. Light collection optics such as fiber optics, lenses, andmirrors are commonly used in various configurations within aspectrometer to direct light from the source to the detector by way of asample. The mode of operation may be diffuse transmission, diffusereflectance, or transflectance. Due to changes in performance of theoverall spectrometer, reference wavelength standards are often scanned.Typically, a wavelength standard is collected immediately before orafter the interrogation of the tissue or at the beginning of the day,but may occur at times far removed such as when the spectrometer wasoriginally manufactured. A typical reference wavelength standard wouldbe polystyrene or a rare earth oxide such as holmium, erbium, ordysprosium oxide. Many additional materials exist that have stable andsharp spectral features that may be used as a reference standard.

The interface of the glucose analyzer to the tissue includes a modulewhere light such as near-infrared radiation is directed to and from thetissue either directly or through a light pipe, fiber-optics, a lenssystem, or a light directing mirror system. The area of the tissuesurface to which near-infrared radiation is applied and the area of thetissue surface the returning near-infrared radiation is detected fromare different and separated by a defined distance and selected to targeta tissue volume conducive for the measurement of the property ofinterest. The patient interface module may include an elbow rest, awrist rest, a hand support, and/or a guide to assist in interfacing theillumination mechanism of choice and the tissue of interest. Generally,an optical coupling fluid is placed on the sampling surface to increaseincident photon penetration into the skin and to minimize specularreflectance from the surface of the skin. Important parameters in theinterface include temperature and pressure.

The sample site is the specific tissue of the subject that is irradiatedby the spectrometer system and the surface or point on the subject themeasurement probe comes into contact with. The ideal qualities of thesample site include homogeneity, immutability, and accessibility to thetarget analyte. Several measurement sites may be used, including theabdomen, upper arm, thigh, hand (palm or back of the hand), ear lobe,finger, the volar aspect of the forearm, or the dorsal part of theforearm.

In addition, while the measurement can be made in either diffusereflectance or diffuse transmittance mode, the preferred method isdiffuse reflectance. The scanning of the tissue can be done continuouslywhen pulsation effects do not affect the tissue area being tested, orthe scanning can be done intermittently between pulses.

The collected signal (near-infrared radiation in this case) is convertedto a voltage and sampled through an analog-to-digital converter foranalysis on a microprocessor based system and the result displayed.

Preprocessing

Several approaches exist that employ diverse preprocessing methods toremove spectral variation related to the sample and instrumentalvariation including normalization, smoothing, derivatives,multiplicative signal correction (Geladi, P., D. McDougall and H.Martens. “Linearization and Scatter-Correction for Near-InfraredReflectance Spectra of Meat,” Applied Spectroscopy, vol. 39, pp.491-500, 1985), standard normal variate transformation (R. J. Barnes, M.S. Dhanoa, and S. Lister, Applied Spectroscopy, 43, pp. 772-777, 1989),piecewise multiplicative scatter correction (T. Isaksson and B. R.Kowalski, Applied Spectroscopy, 47, pp. 702-709, 1993), extendedmultiplicative signal correction (H. Martens and E. Stark, J. PharmBiomed Anal, 9, pp. 625-635, 1991), pathlength correction with chemicalmodeling and optimized scaling (“GlucoWatch Automatic Glucose Biographerand AutoSensors”, Cygnus Inc., Document #1992-00, Rev. March 2001), andFIR filtering (Sum, S. T., “Spectral Signal Correction for MultivariateCalibration,” Doctoral Dissertation, University of Delaware, Summer1998; Sum, S. and S. D. Brown, “Standardization of Fiber-Optic Probesfor Near-Infrared Multivariate Calibrations,” Applied Spectroscopy, Vol.52, No. 6, pp. 869-877, 1998; and T. B. Blank, S. T. Sum, S. D. Brownand S. L. Monfre, “Transfer of near-infrared multivariate calibrationswithout standards,” Analytical Chemistry, 68, pp. 2987-2995, 1996). Inaddition, a diversity of signal, data or pre-processing techniques arecommonly reported with the fundamental goal of enhancing accessibilityof the net analyte signal (Massart, D. L., B. G. M. Vandeginste, S. N.Deming, Y. Michotte and L. Kaufman, Chemometrics: a textbook, New York:Elsevier Science Publishing Company, Inc., 215-252, 1990; Oppenheim,Alan V. and R. W. Schafer, Digital Signal Processing, Englewood Cliffs,N.J.: Prentice Hall, 1975, pp. 195-271; Otto, M., Chemometrics,Weinheim: Wiley-VCH, 51-78, 1999; Beebe, K. R., R. J. Pell and M. B.Seasholtz, Chemometrics A Practical Guide, New York: John Wiley & Sons,Inc., 26-55, 1998; M. A. Sharaf, D. L. Illman and B. R. Kowalski,Chemometrics, New York: John Wiley & Sons, Inc., 86-112, 1996; andSavitzky, A. and M. J. E. Golay. “Smoothing and Differentiation of Databy Simplified Least Squares Procedures,” Anal. Chem., vol. 36, no. 8,pp. 1627-1639, 1964). The goal of all of these techniques is toattenuate the noise and instrumental variation without affecting thesignal of interest.

While methods for preprocessing effectively compensate for variationrelated to instrument and physical changes in the sample and enhance thenet analyte signal in the presence of noise and interference, they areoften inadequate for compensating for the sources of tissue relatedvariation. For example, the highly nonlinear effects related samplingdifferent tissue locations can't be effectively compensated for througha pathlength correction because the sample is multi-layered andheterogeneous. In addition, fundamental assumptions inherent in thesemethods, such as the constancy of multiplicative and additive effectsacross the spectral range and homoscadasticity of noise are violated inthe non-invasive tissue application.

Near-IR Calibration

One noninvasive technology, near-infrared spectroscopy, has been heavilyresearched for its application for both frequent and painlessnoninvasive measurement of glucose. This approach involves theillumination of a spot on the body with near-infrared (NIR)electromagnetic radiation, light in the wavelength range of 700 to 2500nm. The light is partially absorbed and scattered, according to itsinteraction with the constituents of the tissue. With near-infraredspectroscopy, a mathematical relationship between an in-vivonear-infrared measurement and the actual blood glucose value needs to bedeveloped. This is achieved through the collection of in-vivo NIRmeasurements with corresponding blood glucose values that have beenobtained directly through the use of measurement tools such as the YSI,HemoCue, or any appropriate and accurate traditional invasive oralternative invasive reference device.

For spectrophotometric based analyzers, there are several univariate andmultivariate methods that can be used to develop this mathematicalrelationship. However, the basic equation which is being solved is knownas the Beer-Lambert Law. This law states that the strength of anabsorbance/reflectance measurement is proportional to the concentrationof the analyte which is being measured as in equation 3,A=εb C   eq. 3where A is the absorbance/reflectance measurement at a given wavelengthof light, ε is the molar absorptivity associated with the molecule ofinterest at the same given wavelength, b is the distance (or pathlength)that the light travels, and C is the concentration of the molecule ofinterest (glucose).

Chemometric calibration techniques extract the glucose related signalfrom the measured spectrum through various methods of signal processingand calibration including one or more mathematical models. The modelsare developed through the process of calibration on the basis of anexemplary set of spectral measurements known as the calibration set andan associated set of reference blood glucose values based upon ananalysis of fingertip capillary blood, venous, or alternative sitesamples. Common multivariate approaches requiring a set of exemplaryreference glucose concentrations and an associated sample spectruminclude partial least squares (PLS) and principal component regression(PCR). Many additional forms of calibration are well known in the artsuch as neural networks.

Because every method has error, it is beneficial that the primarydevice, which is used to measure blood glucose be as accurate aspossible to minimize the error that propagates through the mathematicalrelationship which is developed. While it appears intuitive that anyU.S. FDA approved blood glucose monitor could be used, for accurateverification of the secondary method a monitor which has an accuracy ofless than 5% is desirable. Meters with increased error such as 10% areacceptable, though the error of the device being calibrated mayincrease.

Currently, no device using near-infrared spectroscopy for thenoninvasive measurement of glucose has been approved for use by personswith diabetes due to technology limitations that include poorsensitivity, sampling problems, time lag, calibration bias, long-termreproducibility, stability, and instrument noise. Fundamentally,however, accurate noninvasive estimation of blood glucose is presentlylimited by the available near-infrared technology, the traceconcentration of glucose relative to other constituents, and the dynamicnature of the skin and living tissue of the patient. Further limitationsto commercialization include a poor form factor (large size, heavyweight, and no or poor portability) and usability. For example, existingnear-infrared technology is limited to larger devices that do notprovide (nearly) continuous or automated measurement of glucose and aredifficult for consumers to operate.

Clearly, a need exists for a completely noninvasive approach to themeasurement of glucose that provides a nearly continuous readings in anautomated fashion.

SUMMARY OF THE INVENTION

The invention involves the monitoring of a biological parameter througha compact analyzer. The preferred apparatus is a spectrometer basedsystem that is attached continuously or semi-continuously to a humansubject and collects spectral measurements that are used to determine abiological parameter in the sampled tissue. The preferred target analyteis glucose. The preferred analyzer is a near-IR based glucose analyzerfor determining the glucose concentration in the body.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a sampling module, a communication bundle and a basemodule;

FIG. 2 shows a preferred embodiment with a grating and detector array;

FIG. 3 shows a preferred embodiment of the sampling module;

FIG. 4 shows a low profile embodiment of the sampling module;

FIG. 5 shows a single filter embodiment of the sampling module;

FIG. 6 shows an alternative embodiment of the sampling module;

FIG. 7 shows noninvasive glucose predictions in a concentrationcorrelation plot;

FIG. 8 shows an LED based embodiment of the sampling module;

FIG. 9 shows a possible LED reflector; and

FIG. 10 shows filter shapes optionally coupled to the LED.

DETAILED DESCRIPTION OF A PREFERRED EMBODIMENT

The presently preferred embodiment of the invention uses a samplingmodule coupled to a base module. The sampling module includes anillumination system based upon an incandescent lamp. The base moduleincludes a grating and detector array. The base module may be connectedto the sampling module through a communication bundle. In this document,the combined sampling module, communication bundle, base module, andassociated electronics and software is referred to as a spectrometerand/or glucose analyzer. In FIG. 1, the sampling module 10 issemi-permanently attached to the forearm of a subject 12, acommunication bundle 14 carries optical and/or electrical signal toand/or from a base module 16 located on a table, and the communicationbundle carries power to the sampling module from the base module.

A block diagram of the noninvasive glucose analyzer is provided in FIG.2. Essential elements of the glucose analyzer are the source 21, guidingoptics 14 before and/or after the sample for coupling the source to thesample and the sample to the detector(s) 23, detector(s) and associatedelectronics 24, and data processing system 25. In FIG. 2, an optionaloptical filter 30, light blocker 31, and standardization material 32 areshown. These components may also be positioned after the sample andbefore the detector. Variations of this simple block diagram are readilyappreciated and understood by those skilled in the art.

The sampling module, base module, and communication bundle are furtherdescribed herein. Key features of the invention may include but are notlimited to:

a semi-permanent patient/instrument interface sampling module 10incorporating at least one of a low profile sampling interface 34, a lowwattage stabilized source 21 in close proximity to the sampled site, anexcitation collection cavity or optics, a guide, a preheated interfacingsolution such as fluorinert, a temperature controlled skin sample, amechanism for constant pressure and/or displacement of the sampled skintissue, a photonic stimulation source, and collection optics or fiber.

In the preferred embodiment the sampling module protrudes less than twocentimeters from the skin measurement site. The sampling module mayinterface with a guide that may be semi-permanently attached to asampling location on a human body. The guide aids in continuously and/orperiodically physically and optically coupling the sampling module tothe tissue measurement site in a repeatable manner with minimaldisturbance. In addition, the guide in combination with the samplingmodule is responsible for pretreatment of the sample site for providingappropriate contact of the sampling device to the skin for the purposeof reducing specular reflectance, approaching and maintainingappropriate skin temperature variation, and inducing skin hydrationchanges. The sampling module preferably collects a diffusely reflectedor transflected signal from the sampled region of skin.

In the preferred embodiment, the base module or semi-remote systemincludes at least a wavelength selection device such as a grating 35 anda detector preferably a detector array with an optional wavelengthreference standard 36 such as polystyrene and an optional intensityreference standard such as a 99% reflective Labsphere® disk. The remotesystem is coupled to the sampling module via a communication bundle 14that carries as least the optical signal and optionally power.Additionally, the communication bundle may transmit control andmonitoring signal between the sampling module and the remote system. Theremote system has at least one of an embedded computer 25, a display 37,and an interface to an external computer system. The remote system maybe in close proximity to the guide element.

In one version of the invention, the sampling module and base module areintegrated together into a compact handheld unit. The communicationbundle is integrated between the two systems.

One version of the sampling module of the invention is presented in FIG.3. The housing 301 is made of silicon. The lamp 302 is a 0.8 W tungstenhalogen source (Welch-Allyn 01270) coupled to a reflector 303. Aphotodiode 309 is used to monitor the lamp and to keep its output stablethrough the use of a lamp output control circuit, especially right afterpower-up. The reflector, and hence the incident light, is centered on anangle six degrees off of the skin's normal to allow room for acollection fiber. The light is focused through a 1 mm thick siliconwindow 306 onto an aperture at the skin. The silicon operates as alongpass filter. The illuminated aperture of the skin has a 2.4 mmdiameter. Positioning onto a sampling site is performed through a guide.The patient sampling module reversibly couples into the guide forreproducible contact pressure and sampling location. Magnets 312 areused in the guide to aid in the positioning of the probe, to ensureproper penetration of the probe into the guide aperture and to enable aconstant pressure and/or displacement interface of the sampled skin 308.The reversible nature of coupling the sampling module into the guideallows the sampling module to be removed and coupled to an intensityreference and/or a wavelength reference that have the same guideinterface and are preferably housed with the base module. The preferredintensity reference is a 99% reflective Labsphere® material and thepreferred wavelength reference is polystyrene. The preferred samplingmodule uses a heater 309 for maintaining the skin at a constanttemperature. A 600 μm detection fiber 310 collects diffusely reflectedlight from the center of the silicon window. The detection fiber iscoated in a manner to block source photons from penetrating through thecladding to the core. For example a metal sheath may be placed aroundthe detection fiber. In this configuration, the length of the detectionfiber is 0.7 meters. The communication bundle includes a power supplyfrom the base unit. A blocking mechanism may be included to allow thedetection of detector dark current or baseline. The base moduleincorporating a grating, detected array, associated electronics, andassociated software is coupled to the sampling module via this bundle.In this configuration, the sampling module extends roughly three inchesfrom the arm.

It should be appreciated that in the preferred embodiment, many of thecomponents are optional and/or variable. Some specific variations aredescribed in this section. It is recognized that the components orproperties discussed in this section may be varied or in some caseseliminated without altering the scope and intent of the invention.

In the preferred embodiment, the base module resides on a table, thesampling module interfaces through a semi-permanently attached guide tothe dorsal aspect of the forearm, and a communication bundle carriespower and optical signal between the two modules. Alternatively, thebase module may be worn on the person, for example on a belt. Thesampling module could couple to any of a hand, finger, palmar region,base of thumb, forearm, volar aspect of the forearm, dorsal aspect ofthe forearm, upper arm, head, earlobe, eye, tongue, chest, torso,abdominal region, thigh, calf, foot, plantar region, and toe. When thebase module is on the table, it may plug into a standard wall outlet forpower. When worn on the person, the module may be battery powered. Whenthe base module is worn on the person, an optional docking station maybe provided as described below for power and data analysis. It is notedhere that the base module may couple directly to the sampling modulewithout a communication bundle. The combined base module and samplingmodule may be integrated into a handheld near-IR based glucose analyzerthat couples to the sampling site through an optional guide.

Sampling Module

The sampling module housing in the preferred embodiment was selected tobe constructed of silicon based upon a number of factors including butnot limited to: providing a minimum of 6 O.D. blocking in theultraviolet, visible, and near-IR from 700 to 1000 nm at a 1 mmthickness, low cost, manufacturability, durability, water resistance,and availability. It is recognized that it is the functionality of thehousing that is important and that the above listed properties may beobtained through a variety of materials such as metals, composites, andplastics without altering the scope and intent of the invention.

The 0.8 W tungsten halogen source is preferred for a number of reasonsincluding but not limited to its power requirements, performancespecifications such as color temperature, spectral output, and lifetimeas well as on parameters such as ruggedness, portability, cost, andsize. It is recognized that the source power is selected based upon thetotal net analyte signal generated and the amount of light reaching thedetection system. It has been determined that the 0.8 W source inconjunction with the aperture and collection fiber of the preferredembodiment provides adequate signal and depth of penetration of thephotons for the indirect determination of glucose using features in the1150 to 1850 nm range. However, sources ranging from 0.05 W to 5 W maybe used in this invention. As described in the alternative embodimentsection, light emitting diodes (LED's) may be used as the source. Thesource is preferably powered by the base module through the connectioncable described below. However, especially with the smaller sources abattery power supply may be incorporated into the sampling module.

A photodiode is used in the preferred embodiment in conjunction withfeedback control electronics to maintain the source at constant poweroutput during data collection which is desirable during dataacquisition. The photodiode is placed before the order sorter (thesilicon longpass filter), in order to detect visible light from thesource. The preferred photodiode is a silicon detector. Other lessdesirable photodiodes include but are not limited to InGaAs, InPGaAs,PbS, and PbSe. This arrangement of components is preferred due to thelow cost, durability, and availability of detectors available in thevisible and near-IR from 700 to 1000 nm where the long pass filterdiscussed below used later in the optical train blocks the opticalsignal used in the feedback loop. The control electronics allow thesource to be driven at different levels at different points in timeduring and prior to data acquisition. In the preferred embodiment, thesource is initially run at a higher power in order to minimize theanalyzer warm-up time. The photodiode and feedback electronics areoptional, but are used in the preferred embodiment. Many spectrometersare common in the art that do not use a separate detector for monitoringthe source intensity.

The source housing/reflector combination in the preferred embodiment wasselected based upon a number of factors including but not limited to:providing acceptable energy delivery to the sample site, reflectivity,manufacturability, ruggedness, size, cost, and providing appropriateheating/temperature control of the sample site. The specific reflectorin the preferred embodiment is parabolic. The properties were optimizedusing standard ray trace software to image the lamp filament onto theaperture defining the sampling location. The optical prescription istuned for a specific spectral range (1100 to 1900 nm) and the coatingsare designed to reflect optimally in this range. It is recognized thatthe reflector may be elliptical or even spherical and that themechanical and optical properties of the reflector may be varied withoutaltering the scope and intent of the invention. For example, in thesimplest embodiment the source may shine light directly onto the sampledsurface without the use of a reflector. In such cases, in order todeliver similar energy to the sampled skin through the aperture, alarger source is required. In another example, the specific focaldistance of the reflector may be varied, which impacts the overalldimensions of the interface without affecting functionality. Similarly,a different substrate may be used as the reflector or metallizedcoatings such as gold, silver, and aluminum may be applied to thesubstrate.

The source/housing reflector in the preferred embodiment may be modifiedto bring in the source light nearly parallel to the skin surface. Oneobjective of a low profile design is to maintain a sampling module thatmay be semi-permanently attached to the sampling site. A low profilesampling module has the benefit of increase acceptance by the consumerand is less susceptible to bumping or jarring during normal wear. Asemi-permanent interface would allow consecutive glucose determinationsin an automated continuous or semi-continuous fashion as describedbelow. Light brought in at a low angle relative to the skin may beturned into the skin with folding optics. A simple mirror may be used;however, a focusing mirror is preferred in order to optimally couplelight into the aperture. A representative embodiment is provided in FIG.4.

One feature that may be used in this embodiment and in the otherembodiments is the use of quick connect optics. In this case a 600 μmfiber 40 is used as the collection optic. The 600 μm fiber is fixed intothe sampling module 41. The sampling module has a connector foraccepting a 300 μm fiber 42 that in turn couples to a slit prior to thegrating in the base module. The coupling of the light may be done bylenses, which may be magnifying or de-magnifying or with folding mirrors44 with appropriate attention to matching numerical apertures. Animportant concept in this design is that the second collection optic isreadily removed from the sampling module allowing the sampling module toremain in contact with the arm. In addition, the quick connect opticallows the user to travel remotely from the base module until the nextreading is desired.

Locating the source and reflector housing near the skin allows fortemperature control/warm-up of the skin. The optical source is a heatsource. Skin temperature is an important variable in near-IR noninvasiveglucose determination. A thermistor 45 sensing the sampling module orpatient skin temperature and feeding this information back to the sourcevia feedback electronics prior to sampling may be used prior spectraldata acquisition in order elevate the skin temperature to a desirablesampling range such as 30 to 40 degrees centigrade. The inclusion of aheater, thermistor, and associated feedback electronics are optional tothis invention. In another embodiment, the skin temperature may bemeasured spectrally by the relative positions of water, fat, and proteinin an acquired near-IR spectrum or through a multivariate analysis.

In the preferred embodiment, an optical filter is placed between thesource and the sampling site. In the preferred embodiment, the opticalfilter is silicon. The silicon window was selected based upon a numberof factors. One factor is that silicon behaves as a longpass filter withblocking to at least six optical density units with a 1 mm thicknessfrom the ultraviolet through the visible to 1000 nm. Second, thelongpass characteristic of silicon acts as an order sorter benefitingthe grating detector combination in the base module. Third, longpasscharacteristics of silicon removes unwanted photons in the ultraviolet,visible, and near-IR that would heat the skin at unwanted depths and toundesirable temperatures due to conversion of the light into heat viathe process of absorbance. Instead, the silicon is heated by thesephotons resulting in maintenance of skin temperature near the surfacevia conduction. Fourth, silicon offers excellent transmissive featuresin the near-IR over the spectral region of interest of 1150 to 1850 nm.Notably, silicon is the same material as the source housing and sourcereflector. Therefore, a single molding or part may be used for all threecomponents. In the preferred embodiment, a silicon window is in contactwith the skin to minimize specular reflectance. In the preferredembodiment, this window is anti-reflection coated based upon propertiesof air on the photon incident side and based upon the optical propertiesof the coupling fluid on the skin surface side of the optic.

Many configurations exist in which the longpass filter is not in directcontact with the skin. First, the longpass filter may be placed afterthe source but not in contact with the skin. For example, the filter maybe placed in or about the pupil plane. In this configuration, photonsremoved by the filter that result in the heating of the filter do notresult in direct heating of the sample site via conduction. Rather, themuch slower and less efficient convection process conveys this heat.This reduces the risk of over heating the skin. Alternatively, twofilters may be placed between the source and the skin. These filters mayor may not be the same. The first filter removes heat as above. Thesecond filter reduces spectral reflectance as above. In a thirdconfiguration, the order sorter nature of the longpass filter iscentral. Silicon removes light under 1050 nm. This allows a grating tobe used in the 1150 to 1850 nm region without the detection of second orhigher order light off of the grating as long as the longpass filter,silicon, is placed before the grating. Therefore, in the thirdconfiguration the longpass filter may be after the sample.

It is recognized that many filter designs exist. In the preferredembodiment a silicon longpass filter is used. The filters may be coatedto block particular regions such as 1900 to 2500 nm,antireflection-coated in order to match refractive indices and increaselight throughput, and/or used in combination with other filters such asshortpass filters. One configuration coats the silicon with a blockerfrom 1900 to 2500 nm. This has the advantage of removing the largestintensity of the blackbody curve of a typical tungsten halogen sourcethat is not blocked by silicon or in the desirable region of 1150 to1850 nm. This blocking band may cover any region from about 1800 nm onup to 3000 nm. Another configuration is a silicon longpass filter usedin combination with an RG glass such as RG-850 that cuts off at about2500 nm. The combination provides a very cost effective and readilyreproduced bandpass filter passing light from approximately 1100 to 2500nm. Notably this filter combination may be used in conjunction with acoating layer such as a blocker from 1900 to 2500 nm in order to providea bandpass from 1100 to 1900 nm. Those skilled in the art will recognizethat there exist multiple configurations of off the shelf and customizedlongpass, shortpass, and bandpass filter that may be placed in one ormore of the locations described above that fulfill the utilityrequirements described above. An alternative embodiment of thesource/reflector/filter is shown in FIG. 5. In this embodiment, siliconis shaped into a parabolic optic 50 surrounding part of the source 51.The outside of the silicon is coated with a reflector 52 such as gold.This embodiment allows a low profile source coupled to the skin. Thetotal height off of the skin may be less than 1 cm with thisconfiguration. The shape of the silicon optic in conjunction withcoating the outside of the silicon with a reflective material such asgold allows efficient coupling of the photons into the skin. Anadditional optional protective coating over the reflector materialallows the silicon optic to also act as a housing for the samplingmodule with the benefits of silicon listed above. Notably, the initialsurface of the silicon (near the source) removes the higher energyphotons that results in heating of the source optics prior to contactwith the skin. The later part of the silicon (near the skin) incombination with a collection fiber acts as a mechanism for reducingspecular reflectance. This configuration eliminates the optional twofilter system as heat and spectral reflectance are dealt with in oneoptic. Essentially, the silicon is acting as a turning optic to allow avery low profile sampling module, as a longpass filter, as an ordersorter, as a heat blocker, as a spectral reflectance blocker, and as avery manufacturable, cheap, and durable component.

An alternative embodiment of the source/reflector/filter is shown inFIG. 6. In this embodiment, the source filament 60 is wrapped around acollection fiber 61. The reflector now directs light into the skinaperture through an optic 62. The optic may be surface coated forreflectance on the incident light surface. Alternatively, as above, thereflector may be transmissive and the outer surface of the reflector maybe reflectively coated. As above, this allow the reflector to act as thehousing. In this embodiment, there exists a filter adjacent to the skinthat in conjunction with a collection optic, fiber, or tube adjacent tothe skin results in the blocking of specular reflectance.

An alternative embodiment combines a broadband source with a singleelement detector without the use of a grating. In one case, aninterferometer composed of two parallel, highly reflecting platesseparated by an air gap may be used. One of the parallel plates may betranslated mechanically such that the distance between the platesvaries. Technically, this is a Fabry-Perot interferometer. When themirror distance is fixed and adjusted for parallelism by a spacer suchas invar or quartz, the system is referred to as a Fabry-Perot etalon.This system allows narrow excitation lines as a function of time.Therefore, no dispersive element is required and a single elementdetector may be used. The interferometer may be placed in one ofmultiple positions in the optical train.

In the preferred embodiment, the illuminated aperture of the skin has a2.4 mm diameter. The aperture in the preferred embodiment was selectedbased upon a number of factors including but not limited to: providingoptical pathlengths within the sample for indirectly monitoring glucoseconcentrations within the body, providing acceptable energy delivery tothe sample site, and providing appropriate heating/temperature controlof the sample site. As discussed below, a fiber optic collection fiberis placed in the center of this illumination area. This allows theincident photon approximately 1 mm of radial travel from the point ofillumination to the collection fiber. This translates into depths ofpenetration that probe water, fat, and protein bands as well asscattering effects that may be used for the indirect determination ofglucose. It is recognized that the dimensions of the aperture need notbe the exact dimensions of the preferred embodiment. An important aspectis the ability to deliver photons to a skin tissue, allow them topenetrate to depths that allow an indirect measurement of glucose, anddetect those photons.

It is recognized that these properties may be varied without alteringthe scope and intent of the invention. For example, the aperture of 2.4mm may be varied. The aperture provides an outer limit of where photonsfrom the source may penetrate the skin. This in turn defines the largestdepth of penetration and optical pathlengths observed. While theaperture may be varied from 1.2 to 5 mm in diameter, the 2.4 mm diameterallows collection of spectra with excellent features for the indirectmeasurement of glucose. At smaller apertures, the average depth ofpenetration of the collected photons decreases. Therefore, variation ofthe aperture affects the net analyte signal of the sampled tissue.Varying aperture shapes are possible as the shape affects thedistribution of photons penetration depth and optical pathlength. Theindirect determination of glucose may be performed off of sampleconstituents such as fat, protein, and water that are distributed as afunction of depth. Therefore, the magnitude of the indirect signalvaries with the aperture. In addition, multiple excitation sites andcollection sites are possible. This could aid, for example, in samplinga representative section of the skin. For example, if one probe waslocated on a hair follicle, the others may be used independently or inconjunction with the first site in order to acquire the analyticalsignal necessary to determine glucose.

Guide

In the preferred embodiment, the entire PIM couples into a guide that issemi-permanently attached to the skin with a replaceable adhesive. Theguide aids in sampling repeatability. The guide is intended to surroundinterfacing optics for the purpose of sampling in a precise location.Typically this is done with an interface surrounding the interfaceprobe. In the main embodiment, the guide is attached for the wakinghours of the subject. A guide may be attached in a more permanentfashion such as for a week or a month, especially in continuousmonitoring glucose analyzers discussed below. The guide allows improvedprecision in sampling location. Precision in sampling location allowsbias to be removed if a process such as mean centering is used in thealgorithm. This is addressed in the preprocessing section below.Additionally, the guide allows for a more constant pressure/constantdisplacement to be applied to the sampling location which also enhancesprecision and accuracy of the glucose determination. While the guidegreatly enhances positioning and allows associated data processing to besimpler and more robust, the guide is not an absolute requirement of thesampling module.

In the preferred embodiment of the invention, magnets are used to aid ina user friendly mechanism for coupling the sampling module to thesampled site. Further, the magnets allow the guide to be reversiblyattached to the sampling module. Further, the guide aids in the opticalprobe adequately penetrating into the guide aperture. In addition, themagnets allow a constant, known, and precise alignment between thesampling probe and the sampled site. In the preferred embodiment twomagnets are used, one on each side of the sampled site, in order toenhance alignment. One or more magnets may provide the same effect. Itis recognized that there exist a large number of mechanical methods forcoupling two devices together, such as lock and key mechanisms,electromagnets, machined fits, VELCRO, adhesives, snaps, and many othertechniques commonly known to those skilled in the art that allow the keyelements described above to be provided. In addition, the magnets may beelectrically activated to facilitate a controlled movement of the probeinto the guide aperture and to allow, through reversal of the magnetpoles, the probe to be withdrawn from the guide without pulling on theguide.

The guide may optionally contain a window in the aperture that may bethe longpass/bandpass filter. Alternatively, the aperture may be filledwith a removable plug. The contact of a window or plug with the skinstabilizes the tissue by providing the same tissue displacement as theprobe and increases the localized skin surface and shallow depthhydration. As opposed to the use of a removable plug, use of a contactwindow allows a continuous barrier for proper hydration of the samplingsite and a constant pressure interface. The use of a plug or contactwindow leads to increased precision and accuracy in glucosedetermination by the removal of issues associated with dry or pocketedskin at the sampling site.

The guide may optionally contain any of a number of elements designed toenhance equilibration between the glucose concentration at the samplingsite and a capillary site, such as the fingertip. Rapidly moving glucosevalues with time can lead to significant discrepancies between alternatesite blood glucose concentration and blood glucose concentration in thefinger. The concentration differences are directly related to diffusionand perfusion that combine to limit the rate of the equilibrium process.Equilibrium between the two sites allows for the use of glucose-relatedsignal measured at an alternate site to be more accurate in predictingfinger blood glucose values.

A number of optional elements may be incorporated into the samplingmodule and/or guide to increase sampling precision and to increase thenet analyte signal for the indirect glucose determination. Theseoptional elements are preferably powered through the base module andconnection cable described below but may be battery operated.Equalization approaches include photonic stimulation, ultrasoundpretreatment, mechanical stimulation, and heating. Notably,equilibration of the glucose concentration between the sampled site anda well-perfused region such as an artery or the capillary bed of thefingertip is not required. A minimization of the difference in glucoseconcentration between the two regionsl aids in subsequent glucosedetermination.

The guide may optionally contain an LED providing photonic stimulationabout 890 nm, which is known to induce capillary blood vessel dilation.This technique may be used to aid in equilibration of alternative siteglucose concentrations with those of capillary blood. By increasing thevessel dilation, and thereby the blood flow rate to the alternate site,the limiting nature of mass transfer rates and their effect on bloodglucose differences in tissue is minimized. The resulting effect is toreduce the differences between the finger and the alternate site bloodglucose concentrations. The preferred embodiment uses (nominally) 890 nmLED's in an array with control electronics set into the arm guide. TheLED's can also be used in a continuous monitoring application where theyare located in the probe sensing tip at the tissue interface. Due to theperiods of excitation required for stimulation, the 890 nm LED ispreferably powered by a rechargeable battery in the guide so that theLED may be powered when the communication bundle is not used.

The guide may optionally contain an apparatus capable of deliveringultrasound energy into the sample site. Again, this technique may beused to aid in equilibration of alternative site glucose concentrationswith those of capillary blood by stimulating perfusion and/or bloodflow.

The guide may optionally contain an apparatus that provides mechanicalstimulation of the sampled site prior to spectral data acquisition. Oneexample is a piezoelectric modulator than pulses in an out relative tothe skin surface a distance of circa 20 to 50 μm in a continuous or dutycycle fashion.

The guide may optionally contain a heating and/or cooling element, suchas a strip heater or an energy transfer pad. Heating is one mechanism ofglucose compartment equilibration. These elements may be used to matchthe core body temperature, to manipulate the local perfusion of blood,to avoid sweating and/or to modify the distribution of fluids among thevarious tissue compartments.

It is recognized that the sampling module can interface directly to askin sampling without the use of a guide.

In the preferred embodiment of the invention, a coupling fluid is usedto efficiently couple the incident photons into the tissue sample. Thepreferred coupling fluid is fluorinert. Different formulations areavailable including FC-40 and FC-70. FC-40 is preferred. While manycoupling fluids are available for matching refractive indices,fluorinert is preferred due to its non-toxic nature when applied to skinand due to its absence of near-IR absorbance bands that would act asinterferences. In the preferred embodiment, the coupling fluid ispreheated to between 90 and 95° F., preferably to 92° F. Preheating thecoupling fluid minimizes changes to the surface temperature of thecontacted site, thus minimizing spectral changes observed from thesampled tissue. The coupling fluid may be preheated using the sourceenergy, the optional sample site heater energy, or through an auxiliaryheat source. Preheating FC-70 is preferable due to its poorer viscosity.The preheated FC-70 is not as likely to run off of the sample site.Automated delivery prior to sampling is an option. Such a system couldbe a gated reservoir of fluorinert in the sample module. Manual deliveryof the coupling fluid is also an option, such as a spray bottle deliverysystem. Coverage of the sample site is a key criteria in any deliverysystem.

In the preferred embodiment of the invention, the sampling site is thedorsal aspect of the forearm. In addition, the volar and ventral aspectof the forearm are excellent sampling locations. It is furtherrecognized that the guide may be attached to other sampling locationssuch as the hand, fingertips, palmar region, base of thumb, forearm,upper arm, head, earlobe, chest, torso, abdominal region, thigh, calf,foot, plantar region, and toes. It is preferable but not required tosample regions of the skin that do not vary due to usage as with thefingertips or near joints, change with time due to gravity like the backof the upper arm, or have very thick skin such as the plantar region, orabdominal region.

There are a number of possible configurations for collection optics. Inthe preferred embodiment, light is incident to the sample through thelongpass filter which is in contact with the skin. In the preferredembodiment, there exists a hole in the middle of the longpass filter. Acollection fiber is placed into the hole in contact with the skin. Thisconfiguration forces incident photons into the sampled skin prior tocollection into the fiber optic. If the fiber optic were merely pushedup against the filter, then light could bounce through the filterdirectly into the collection fiber without entering the skin resultingin a spectral reflectance term. Once the collection fiber is in contactwith the skin, the signal (or rather absence of observed intensity) atthe large water absorbance bands near 1450, 1900, and 2500 nm may beused to determine when the apparatus is in good spectral contact withthe sampled skin. The preferred collection optic is a single 600 μmdetection fiber. It is recognized that the hole and the fiber may bealtered in dimension to couple in another sized fiber such as a 300 μmdetection fiber. As those skilled in the art will appreciate, the fiberdiameter is most efficient when it is optimally optically coupled to thedetection system. Therefore, as detector systems slits and detectorelement sizes are varied, the collection optics should also be varied.The center collection fiber of 600 μm combined with the aperture of 2.4mm is related to a central fiber collecting incident light from abundle. The collection optic is not necessarily limited to a fiberoptic. Additional configurations include but are not limited to a lightpipe or a solid piece of optical glass.

In the preferred embodiment, the collected signal is turned 90° off axisto send the signal roughly parallel to the arm in order to minimize theheight of the sampling module. This may be accomplished by such commonmeans as a folding mirror or bending of a fiber optic, as describedabove.

In one embodiment, the collected light is coupled to a second collectionthat connects at its opposite end to the base module. The purpose ofthis configuration is to allow the sampling module to be worn on theperson without the bulk of the rest of the spectrometer here referred toas the base module. A quick connect connector is used to allow rapidconnection of the base module to the sampling module in a reproducibleand user friendly fashion. The connecting cable carries at least theoptical signal. In the preferred embodiment, the connection cable alsocarries power to the source and optional elements, such as thethermistor, heater, or sample compartment glucose concentrationequilibration apparatus. This connector also allows the diameter of thecollection fiber to be changed. For example, the 600 μm collection fibermay be downsized to a 300 μm connection fiber with appropriate attentionto coupling optics and numerical apertures obvious to those skilled inthe art. Some advantages of the smaller diameter connection fiber aredescribed here. First, the smaller diameter fiber has a tighter bendradius. Second, if a slit is used prior to the spectrometer then thefiber can be made of appropriate dimension for coupling to the slit.Third, the smaller diameter fiber is less susceptible to breakage. Anadditional consideration is cost.

It is recognized that collection/detection elements may be recessed awayfrom the window in order to avoid the direct detection of surfacereflectance. It is further recognized that coupling fluids may be usedto increase the angle of collection to the detection element.

Base Module

In the preferred embodiment, the base module includes at least aspectrometer (grating and detector system). The grating is optimized todeliver peak energy about 1600 nm. The detector is an InGaAs arraycovering the range of 1100 to 1900 nm. A main purpose of thespectrometer is wavelength separation and detection. Variations in thegrating/detector system are readily understood by those skilled in theart.

In an alternative embodiment, a broadband source is combined with adetector array without the use of a dispersive element. In one case,filters are placed in from the detectors. One type of filter are thindielectric films, such as in Fabry-Perot interference filters. Thesefilters may be placed into a linear, bundle, or rectangular patterndepending upon how the light is coupled to the detector. For example, aslit may be used in conjunction with a rectangular array of filters anddetectors. Alternatively, a fiber may be used in conjunction with abundle of filters and associated detectors. Another type of filter is alinear variable filter. For example, a linear variable filter may sit infrom of a linear array of filters. Many variations on these opticallayouts are known to those skilled in the art.

The Power/Control Module may be coupled to the user's belt or otherlocation other than the measurement site. In an alternate embodiment thepatient interface module contains a battery and two-way wirelesscommunication system. In this configuration the Control/Power module maybe carried by the patient. For example, a handheld computer or Palmcomputing platform can be equipped with a two-way wireless communicationsystem for receiving data from the patient interface module and sendinginstructions. The computer system then provides the system with analysiscapabilities.

In an alternate embodiment the base module contains a battery andtwo-way wireless communication system. In this configuration theControl/Power module is contained a remote location that is eithercarried by the patient or not. For example, a handheld computer or Palmcomputing platform can be equipped with a two-way wireless communicationsystem for receiving data from the patient interface module and sendinginstructions. The computer system then provides the system with analysiscapabilities.

The Control/Power Module contains the control electronics, power system,batteries, embedded computer and interface electronics. Controlelectronics provide a means for initiating events from the embedded orattached computer system and interfacing the detector electronics(amplifiers) which provide a voltage that is related to the detectedlight intensity. Digitizing the detected voltage through the use of ananalog-to-digital converter is performed. The signals detected are usedto form a spectrum which is represents the diffusely reflected anddetected light intensity versus wavelength. In addition, historicalmeasurements are made available through a display and/or an externalcommunication port to a computer or computer system, e.g. a Palmtop. Inan alternate embodiment, the measurement and ancillary information istransferred to a remote display and receiving unit, such as a handheldcomputer or stand-alone display module through a wireless communication.In this latter system, a display and receiving unit may be incorporatedinto a watch, pen, personal desktop assistance, cell phone, or bloodglucose monitoring device.

Spectrometer

It is here noted, that variation of one component may affect optimal orpreferred characteristics of other components. For example, variation inthe source may affect the quality or design of the reflector, thethickness of the filter, the used aperture size, the time or powerrequirements for maintaining or heating the skin and/or fluorinert, andthe diameter of the collection fiber. Similarly, changing anothercomponent such as the collection fiber diameter impacts the otherelements. Those skilled in the art will appreciate the interaction ofthese elements. Those skilled in the art will also immediatelyappreciate that one or more components of the spectrometer may bechanged without altering the scope of the invention.

Important regions to detect are permutations and combinations of bandsdue to water centered about 1450, 1900, or 2600 nm, protein bandscentered about 1180, 1280, 1690, 1730, 2170, or 2285 nm, fat bandscentered about 1210, 1675, 1715, 1760, 2130, 2250, or 2320 nm, orglucose bands centered about 1590, 1730, 2150, and 2272 nm.

A preferred physical orientation of the spectrometer is in a verticalposition. For example, when sampling on the dorsal aspect of the forearmwhen the palm is face down on a support it is preferable for thesampling module to come down onto the arm from above. This allows theweight of the sampling module to be reproducible.

Standards

Near-infrared devices are composed of optical and mechanical componentsthat vary due to manufacturing tolerances, vary in optical alignment,and change with time due to mechanical factors such as wear and strain,and environmental factors such as temperature variation. This results inchanges in the x-axis of a given spectrometer with time as well asinstrument-to-instrument variation. When a calibration model is used toextract information about a sample, such as the glucose concentration inthe body, these instrument related changes result in wavelengthuncertainty that reduces the accessibility of the signal related to theproperty of interest. These variations also degrades the device accuracywhen a calibration model is transferred from one instrument to another.

A system for standardizing the wavelength axis of near-IR opticalsystems that measures light at a multiplicity of wavelengths isdescribed in this section. The preferred embodiment is that presented inFIG. 2. The system described in this section may be used with theinstrument configurations described in the remainder of this document.The spectrometer system detects the transmitted or reflectednear-infrared radiation from the sample within a specified wavelengthrange and the analyzer determines the absorbance at various wavelengthsafter a standardization procedure. Methods for standardizing the x-axisof a spectrometer based system rely on a comparative analysis of amaster and slave spectra of a standardization material. A material withabsorption bands in the targeted wavelength region is used fordetermining the x-axis. Typically, the reference or standard absorbancebands are reasonably sharp, stable, and distributed across thewavelength region of interest (1100 to 1900 nm). Common materials forthis purpose are polystyrene, erbium oxide, dysprosium oxide, andholmium oxide though a large number of plastics may be used. Internalpolystyrene has been used as a reference in the FOSS, formerlyNlRSystems spectrometers. However, in these systems, polystyrene is usedin conjunction with an actuated rotating grating and a single detector.In the preferred embodiment of this invention no actuated grating isused.

The material used for standardization may be measured external to thespectrometer system with an external mounting system. However, thematerial mounted in a separate standard mounting system external to thespectrometer must be placed on the device by the user at designated timeperiods. This process is subject to positioning error and increases thecomplexity of the measurement protocol from the standpoint of the user.This is particularly a problem in consumer oriented devices, such asnon-invasive glucose sensors, in which the user may not be technicallyoriented.

Alternatively, the reference may be continuously mounted internal to theinstrument in a separate light path. In this configuration, the internalwavelength standard may be measured simultaneously with the sample.Alternatively, the reference may be moved through an actuator into themain optical train at an appropriate time, optionally in an automatedprocess. In either of these systems, the reference spectrum may becollected in transmittance of reflectance mode. However, it ispreferable to collected an external reference in diffuse reflectancemode. For example a polystyrene disk placed at an angle to the incidentlight to minimize specular reflectance may be backed by a reflector suchas a Labsphere® reference. For an internal reference, a similararrangement may be used, but a transmittance spectrum is preferred.

The wavelength standardization system includes associated methods formeasurement of a reference spectrum and a (wavelength) standardizationspectrum through the spectroscopic measurement of a non-absorbingmaterial and a material with known and immutable spectral absorbancebands respectively. The spectrum of the standardization material is usedin-conjunction with an associated method for standardizing the x-axis ofsample spectra that are collected subsequently. The method includes amaster spectrum of the standardization material and a method fordetermining the discrepancy between the master and instrumentstandardization spectrum. The master spectrum and the wavelength regionsare stored in nonvolatile memory of the instrument computer system. Onemethod of calculating the phase difference or x-axis shift between themaster and slave spectra is through the use of cross correlation. Forexample, one or more windows across the spectrum the x-axis phase shiftbetween the master and acquired spectrum are determined through across-correlation function after removing instrument related baselinevariations. The phase shift is used to correct (standardize) the x-axisof the acquired spectrum to the master spectrum. Other approachesinclude interpolation or wavelet transformation.

Preprocessing

After conversion of the photons into intensity and optionally absorbanceunits, preprocessing occurs. The detected spectrum may be processedthrough multiple preprocessing steps including outlier analysis,standardization, absorbance calculation, filtering, correction, andapplication to a linear or nonlinear model for generation of an estimate(measurement) of the targeted analyte or constituent which is displayedto the user.

Of particular note is the preprocessing step of bias correcting thespectral data collected in one or both of the X (spectra) and Y (glucoseconcentration) data. In particular, the first scan of a day may have areference glucose concentration associated with it. This glucoseconcentration may be used as a bias correction for glucosedeterminations collected until subsequent calibration. Similarly, thefirst spectrum of the day may be used to adjust calibration componentsfrom the X block. Notably, the guide allows the same sampling locationto be obtained until the guide is removed. This directly impacts the useof the first spectrum and reference glucose concentration to adjust themodel in terms of preprocessing and subsequent model application.

Additional preprocessing techniques are covered in the introductorysection. These techniques are well understood by those skilled in theart.

Modeling

Subsequent data analysis may include a soft model or a calibration suchas PCR or PLS. Many other modes of data analysis exist such as neuralnetworks. A method has been invented for calibrating the device to anindividual or a group of individuals based upon a calibration data set.The calibration data set is comprised of paired data points of processedspectral measurements and reference biological parameter values. Forexample, in the case of glucose measurement, the reference values areone or more of the following: finger capillary blood glucose, alternatesite capillary blood glucose, i.e. a site on the body other than thefinger, interstitial glucose or venous blood glucose. The calibrationdata is subject to optimal sample selection to remove outliers, datacorrelating to ancillary factors and data with excessive variation.Spectral measurements are preprocessed prior to calibration throughfiltering and scattering correction and normalized to a backgroundtemplate collected each time the guide system is attached to the skintissue. Measurements are performed after preprocessing data collectedsubsequent to calibration as discussed above through the calibration ormodel to measure the variation of the biological parameter relative toits value at the time the guide was attached. The scope of thesetechniques was addressed in the prior art section and are well known tothose skilled in the art.

Results of a study using a noninvasive glucose analyzer are presentedhere. The study used a custom built noninvasive near-IR glucoseanalyzer. The analyzer is conceptually as presented in the preferredembodiment with components including a tungsten halogen source, aback-reflector, a bandpass optical filter, a fiber optic illuminationbundle, a guide, a fluorinert coupling fluid, a guide, an aperture, aforearm sampling site, a collection fiber, a slit, a dispersive grating,and an InGaAs array detector though the spectrometer was larger inoverall dimensions than in the preferred embodiment. However, theminiaturized sampling module has been demonstrated to deliver equivalentenergy to the sample site. A calibration model was built. A subsequentprediction data set was initiated two weeks after all parameters werefixed in the calibration model. Subsequent prediction data (spectra)were collected with two spectrometers on seven people over a period ofseven weeks. Preprocessing included a Savitsky-Golay first derivativewith 27 points and mean centering. A PLS model was applied with afifteen factor model to the resulting data over a range of 1200 to 1800nm. A total of 976 glucose determinations were made. The outlieranalysis program was automated. The results are presented in FIG. 7 in aconcentration correlation plot overlaid with a Clarke error grid.Overall, 99.9% of the glucose predictions fell into the ‘A’ or ‘B’region of the Clarke error grid. These glucose predictions areconsidered clinically accurate.

Docking Station

In the preferred embodiment, the base module is integrally connected tothe docking station. In addition to the grating, detector assembly, andpower supply, the docking station includes a computer and a glucosemanagement center. The glucose management system may keep track ofevents occurring in time such as glucose intake, insulin delivery, anddetermined glucose concentration. These may be graphed with time orexported to exterior devices, such as a doctor's computer.

A process is provided for estimating the precision of the measurementthrough a statistical analysis of repeated or successive measurements. Amethod is implemented for determining when the biological parameter isclose to a preset level through a statistical estimate of the confidencelimits of a future analyte prediction. The prediction is made through asimple slope, e.g. change in the biological parameter over the change intime, estimate based on an exponentially moving average and theconfidence limits are based upon the estimate of precision. Alternately,the prediction is made through a standard time series analysis. An alarmis invoked if the associated present alarm level is within theconfidence interval of a future biological parameter prediction. Thisprocess is used, for example, to detect the potential for hypoglycemiain diabetics in the near future, e.g. within 10-30 minutes. In addition,the process is used to detect potential outliers through a determinationof the statistical consistency of a particular measurement with itsexpected value.

Continuous/Semi-Continuous Glucose Determination

Continuous or semi-continuous measurements may be taken when thesampling module is in contact with the sampling site. Measurements of abiological parameter that are made at short intervals relative to thechange in the biological parameter such that the measurement process iscontinuous. In the preferred embodiment, measurements may be made everysix seconds. Realistically, the glucose concentration does not change toa measurable level within six seconds. Therefore, readings taken at aless frequent interval such as every 1, 5, 10, 20, 30, or 60 minutes canbe made. Readings taken at this interval are still referred to ascontinuous and/or semi-continuous. The continuous readings may beperformed in an automated fashion.

It is noted that when the biological parameter is slowly varying, theguide can remain attached to the individual while the rest of the systemis intermittently attached at particular intervals to make continuous orsemi-continuous readings.

An element of the invention is the use of the time based information andtrends to perform other functions such as estimate of the precision,confidence intervals and prediction of future events.

A process is provided for estimating the precision of the measurementthrough a statistical analysis of repeated or successive measurements. Amethod is implemented for determining when the biological parameter isclose to a preset level through a statistical estimate of the confidencelimits of a future analyte prediction. The prediction is made through asimple slope, e.g. change in the biological parameter over the change intime, estimate based on an exponentially moving average and theconfidence limits are based upon the estimate of precision. Alternately,the prediction is made through a standard time series analysis. An alarmis invoked if the associated present alarm level is within theconfidence interval of a future biological parameter prediction. Thisprocess is used, for example, to detect the potential for hypoglycemiain diabetics in the near future, e.g. within 10-30 minutes. In addition,the process is used to detect potential outliers through a determinationof the statistical consistency of a particular measurement with itsexpected value.

In circumstances in which the Control/Power module can be securedwithout disturbing the sample site the two modules are merged into onethat are attached to the subject through the guide interface system.Finally, when the biological parameter is slowly varying, the guide canremain attached to the individual while the rest of the system isintermittently attached at particular intervals.

A link is disclosed to an insulin delivery system. When the monitoredbiological parameter is glucose, a link is provided to an insulindelivery system to provide a feedback mechanism for control purposes.The link is either a direct or a wireless connection. In addition, acommunication system is provided for transmitting the patient'smonitored glucose levels to his physician.

AN ALTERNATIVE EMBODIMENTS

As in the preferred embodiment, a primary alternative embodiment of theinvention includes two main modules: a sampling module and base moduleconnected though a communication bundle. The modules are as described inthe preferred embodiment with the exception of the source and theassociated wavelength selection/detection components. In the alternativeembodiment of the invention, the spectrometer system uses LEDs to bothprovide near-infrared radiation to the sample and to perform wavelengthselection over predefined wavelength ranges. This embodiment has thesignificant advantage of not requiring a dispersive element orinterferometer based system for the purpose of wavelength selection.Rather, each LED provides near-infrared radiation over a band ofwavelengths and thereby gives the necessary means for wavelengthselection.

The wavelengths of the LEDs are selected specifically to optimize thesignal-to-noise ratio of the net analyte signal of the target analyteand are arranged at various distances with respect to the detectionelements to provide a means for sampling various tissue volumes for thepurpose of averaging and the determination of a differentialmeasurement. The LEDs are sequentially energized one at a time and/or ingroups to obtain various estimates of the diffuse reflectance of varioustissue volumes at specific wavelengths or bands of wavelengths. Inaddition, the LEDs can be pulsed to provide short measurements with highsignal-to-noise ratios. This provides greater illumination intensity,while avoiding photo heating of the sampled tissue volume. Alternately,the LEDs can be modulated at a particular duty cycle and frequency toprovide a means for removing additive noise and simultaneous measurementof multiple wavelengths.

The wavelengths of the LED(s) are selected specifically to optimize thesignal-to-noise ratio of the net analyte signal of the target biologicalparameter and are arranged at various distances with respect to thedetection elements to provide a means for sampling various tissuevolumes for the purpose of averaging and the determination of adifferential measurement. The LEDs are sequentially energized one at atime and/or in groups to obtain various estimates of the diffusereflectance of various tissue volumes. In addition, the LEDs can bepulsed to provided short measurements with a high signal-to-noise ratiowhile avoiding photo heating of the sampled tissue volume. Alternately,the LEDs can be modulated at a particular duty cycle and frequency toprovide a means for removing additive noise and simultaneous measurementof multiple wavelengths.

With an LED source, the remainder of the spectrometer remains as in thepreferred embodiment and its species. For example, the LED's may bestabilized with control electronics, optics may be used to guide thesource intensity to the sampled aperture, a guide may be used, acoupling fluid may be used, temperature stabilization of the source andor sample may be used, collection optics integrate with the sampled skindirectly, a communication bundle may be employed, and a base module isused with or without a docking station. As in the preferred embodiment,the detector may stare directly at the tissue.

EMBODIMENTS

A number of instrument configurations of the alternative embodiment arepresented below. Those skilled in the art will recognize thatpermutations and combinations of these embodiments are possible.

In the simplest embodiment, the LEDs may illuminate the sample directly,as in FIG. 8. In FIG. 8, a coupling fluid 84, as disclosed above, isshown provides between the device and the tissue sample. An optionalmixing chamber with a reflective surface may be used between the LEDs 80and the optical window 81 to provide a nearly uniform distribution ontothe tissue region 82 surrounding the detection fiber 83. A spacer 85 mayalso be provided between the fiber and the LEDs. In this embodiment, theLEDs are designed with a bandwidth enabling the measurement, and theLEDs are arranged in a manner that allows the sampling and detection ofa particular tissue volume at a particular band of wavelengths. Each LEDmay be recessed into a material 91 having a reflective surface 90 asshown in FIG. 9.

In this scenario, two arrangements are used. First, a mixing chamber ispresent as shown in FIG. 8 with the filter inserted in the place of theoptical window. This allows the LED's to be used in much the same way asa broadband source.

Second, the illumination-to-detection distance may be used formeasurement purposes so the mixing chamber is removed and the LEDs areput in close proximity or even touching the overall sampling site viaoptional filters. In this second mode, the distance from theillumination spot of the LED to the collection optics is known. Thisallows the average depth of penetration of the photons and averagepathlength to be known. This allows wavelength dependent scanning ofdepth and radial variation from the collection spot, and allowswavelength specific information to be used in an indirect reading of theglucose concentration.

In the preferred embodiment, groups of LEDs (FIG. 10; 100) are employedwith each group associated with a single filter type, more than onephysical filter may be necessary. The LEDs are arranged at distancessurrounding the detection fiber and energized according to a strategyenabling the detection of light associated with different wavelengthbands and different illumination to detection distances (se e FIG. 10).In one embodiment (FIG. 10 a) the groups of LEDs are arranged in annuli(rings) at specific distances surrounding the detection fiber. Thefilters are arranged in rings surrounding the detection fiber andcovering the associated LEDs. Each annular ring of the filter may haveits own filter characteristics. In a second arrangement (FIG. 10 b),groups of LEDs are arranged in wedges surrounding the detection fiber.In the second embodiment the filters may be of a wedged or triangularshape and are arranged to cover their associated LEDs. Each wedge filtermay have its own filter characteristics.

In another embodiment, each LED or group of LEDs has an associatedoptical filter that is used to limit the bandwidth of emitted light. Adifferent filter is mounted such that the light emitted and delivered tothe sample from the LED passes through the filter. The filter associatedwith an LED is designed with a specific bandwidth and is centered on aparticular wavelength that is within the native bandwidth of the LED. Toprovide for a broader illumination pattern or to increase the lightenergy delivered to the sample, groups of LEDs can be associated withthe same filter. Through alternate energization of the LEDs or bymodulating each LED or LED group at different frequencies (anddemodulating after detection), narrow wavelength bands on the order of5-100 nm can be distinguished and measured through a single elementdetector.

In another embodiment, the LEDs have a bandwidth relatively broader thanthe net analyte and interference signals. The light collected by thedetection fiber is passed through a slit and imaged onto dispersiveelement which disperses the band of detected light onto an array ofdetector elements. In this configuration, optical filters on the LEDsare not employed.

In another embodiment, the LED's are used in a spectrometer without adispersive element and a single element detector. In one case, thindielectric films are used as in Fabry-Perot interference filters. Afilter is associated with each LED. In a second case, an interferometercomposed of two parallel, highly reflecting plates separated by an airgap may be used. One of the parallel plates may be translatedmechanically such that the distance between the plates varies.Technically, this is a Fabry-Perot interferometer. When the mirrordistance is fixed and adjusted for parallelism by a spacer such as invaror quartz, the system is referred to as a Fabry-Perot etalon. Both casesallow narrow excitation lines and may be used by sequentially firing theLED's as above.

A number of spectrometer configurations are possible for thismeasurement as are outlined above. Basically the spectroscopicmeasurement system includes a source of near-infrared radiation, awavelength selection system, an interface to the patient, photon guidingoptics, and a detector.

Although the invention has been described herein with reference tocertain preferred embodiments, one skilled in the art will readilyappreciate that other applications may be substituted for those setforth herein without departing from the spirit and scope of the presentinvention. Accordingly, the invention should only be limited by theclaims included below.

1. An apparatus for noninvasive measurement of an analyte property usingnear-infrared spectroscopy, comprising: a sample module; a base modulephysically separated from said sample module; a communication bundle forcoupling said base module to said sample module; a source located in atleast one of said base module and said sample module; a first opticlocated in an optical train after said source, for removing photonicheat energy from said optical path; and a second optic located in saidoptical train after said first optic and before a sample site.
 2. Theapparatus of claim 1, said second optic substantively contacting an areaabout said sample site and aiding in mechanical stabilization of acollection optic, said collection optic being positioned in closeproximity to said sample site to reduce specular reflectance.
 3. Theapparatus of claim 1, said communication bundle carrying any of: any ofoptical and electrical signals between said base module and said sample;and power between said sample module and said base module.
 4. Theapparatus of claim 1, at least one of said base module and said samplemodule further comprising a detector array.
 5. The apparatus of claim 4,wherein said detector array is optically coupled to a grating.
 6. Theapparatus of claim 5, wherein at least one of said first optic and saidsecond optic removes source light otherwise detected by said detector assecond order from of said grating.
 7. The apparatus of claim 1, saidanalyte property comprising: glucose concentration.
 8. The apparatus ofclaim 7, said analyzer either continuously or semi-continuouslymonitoring said glucose concentration.
 9. The apparatus of claim 7,further comprising: means for bias correcting at least one of spectra(X) and glucose concentration data (Y).
 10. The apparatus of claim 1,said sample module performing either continuous or semi-continuousautomated sampling of said sample site, wherein time between samplingcomprises any of about 1, 5, 10, 20, 30, and 60 minutes.
 11. Theapparatus of claim 1, said source comprising an incandescent lamp. 12.The apparatus of claim 1, said source comprising at least one lightemitting diode.
 13. The apparatus of claim 1, further comprising areflector for reflecting light from said source toward said sample site.14. The apparatus of claim 1, wherein skin temperature is measuredspectrally using an acquired spectrum and multivariate analysis.
 15. Theapparatus of claim 1, further comprising: an optical coating on at leastone of said first optic and said second optic, wherein said opticalcoating comprises any of: an antireflection coating; a longpass filter;and a shortpass filter.
 16. The apparatus of claim 1, furthercomprising: an aperture defined at a sample module/sample site interfaceproviding an optical opening of between about 1.2 and 5 millimeters. 17.The apparatus of claim 7, further comprising: means for enhancingequilibration in glucose concentration between said sample site andfinger blood glucose concentration.
 18. The apparatus of claim 1,further comprising: means for automated delivery of a coupling fluid tosaid sample site prior to sampling.
 19. The apparatus of claim 1,further comprising: an optical collection fiber inserted into anaperture formed in said second optic.
 20. The apparatus of claim 1,further comprising: means for optically detecting contact of said samplemodule with said sample site.
 21. The apparatus of claim 1, furthercomprising: a user wearable power/control module coupled to said source.22. The apparatus of claim 1, wherein said sample module protrudes lessthan two centimeters from said sample site.
 23. The apparatus of claim1, wherein said base module is coupled directly to said sample module,with said communication bundle forming an integral part thereof.
 24. Theapparatus of claim 1, said sample module further comprising: aFabry-Perot interferometer.
 25. The apparatus of claim 1, furthercomprising: means for performing an indirect determination of glucoseconcentration from sample constituents which comprise any of: fat,protein, and water; wherein said sample constituents are distributed asa function of depth in a sample.
 26. The apparatus of claim 1, furthercomprising: means for measuring a reference spectrum and a wavelengthstandardization spectrum through spectroscopic measurement of aminimally absorbing substance and a material with known and immutablespectral absorbance bands.
 27. The apparatus of claim 1, said basemodule further comprising: means for calibrating to an individual or agroup of individuals based upon a calibration data set comprised ofpaired data points of processed spectral measurements and referencebiological parameter values.
 28. The apparatus of claim 1, furthercomprising: a docking station with which said base module is integrallyconnected, said docking station comprising a computer and an analyteproperty management center; wherein said analyte property managementcenter keeps track of events occurring over time.
 29. The apparatus ofclaim 1, further comprising: means for taking any of continuous andsemi-continuous measurements when said sample module is in proximatecontact with said sample site.
 30. A method for noninvasive measurementof an analyte property using near-infrared spectroscopy, comprising thesteps of: providing an analyzer for collecting a near-infrared spectrumof a human tissue sample site; and estimating said analyte propertythrough application of a multivariate calibration model on saidspectrum, the step of providing said analyzer comprising the steps of:providing a sample module; providing a base module that is physicallyseparated from said sample module; providing a communication bundle forcoupling said base module to said sample module; providing a sourcelocated in at least one of said base module and said sample module;providing a first optic located in an optical train after said source,for removing heat energy from said optical train; and providing a secondoptic located in said optical train after said first optic and before asample site.